john e. wagner, m.d. - fa research...
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Blood and Marrow Transplant for FA John E. Wagner, M.D.
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175
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0 1976 1979 1982 1985 1988 1991 1994 1997 2000 2003 2006 2009 2012 2015
Cum ulative
175
150
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0
Cum ulative
U R D R D
Num
ber o
f Tra
nspl
ants
1st Umbilical cord blood transplant
1st T cell depletion for URD BMT
Dose reduced therapy
High dose therapy
TBI dose de- escalation study
1st use of fludarabine
1st successful PGD/IVF
Next steps
Elimination of MP (Siro/MMF)
Accomplishments (n=226)
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Tissue Repair
Quality of Life
Cancer Prevention
Immune system Other tissues
Curing Fanconi Anemia
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Grand Challenges
• Universal donor availability
• Reliable engraftment
• Absence of GVHD
• Prompt immune recovery
• Minimal late effects
• Earlier diagnosis / referral
- Done (BM/UCB)
- Done (FLU)
- Better (TCD)
- Needs work
- Better
- Improving
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University of Minnesota Referral
• Confirmatory DEB / MMC
• HLA typing
• Evaluation of siblings (DEB / HLA)
• Q3M CBC / Q1Y BMA-BX (cytogenetics)
• Organ / endocrine evaluation
• Reproductive / genetic counseling
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University of Minnesota Treatment Options by Disease Status and
Donor Type
Aplastic Anemia MDS/Leukemia
FLU-CY CY-FLU-TBI 300 cGy
HLA matched sibling
Alternative donor type
Aplastic Anemia MDS/Leukemia
CY-FLU-TBI 300 cGy [BU-FLU-CY if BRCA2]
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If no HLA matched sibling Best Available Donor
Diagnosis
Search
HLA 8/8
HLA 7/8
Bone Marrow
Peripheral Blood
Cord Blood
HLA 6/6
HLA 5/6
>3.0
>4.0
2 weeks 3-4 mos
University of Minnesota
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Cleave the bead from the cells
Prevention of GVHD
T cell depletion
CD34+ cells University of Minnesota
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Matched Sibling Donor HSCT For FA/SAA
-5 -4 -3 -2 -1 0 1 2 3
CY 5 HSCT
FLU 35
ATG ATG ATG ATG ATG
G-CSF
(ANC 2500)
CSA (Day 100)
(Day -5 to 15) MP
University of Minnesota
TCD BM
UCB Eliminated Radiation TCD to reduce risk of GVHD
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Matched Sibling Donor HSCT For FA/SAA
-5 -4 -3 -2 -1 0 1 2 3
CY 5 HSCT
FLU 35
ATG ATG ATG ATG ATG
G-CSF
(ANC 2500)
CSA (Day 100)
(Day -1 to 30) MMF
University of Minnesota
TCD BM
UCB
Eliminated Radiation TCD to reduce risk of GVHD Eliminated MP
11/2011
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Cum
ulat
ive
prop
ortio
n
• 100% engraftment • 0% severe RRT • 3% acute GVHD (1 patient) • 0% chronic GVHD
0 2 4 6 8 10 12
Months after HSCT
0.0
0.2
0.4
0.6
n=28 0.8
1.0
14 16 18 20 22 24
97%
Survival Patients <18 years with a genotypic identical donor
One with grade 3 GVHD
COD infection due to GVHD
University of Minnesota
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-6 -5 -4 -3 -2 -1 0 1 2 3
CY10 CY10 CY10 CY10 HCT
UCB
TCD BM
FLU 35 FLU 35 FLU 35 FLU 35
ATG ATG ATG ATG ATG
TBI 300
Unrelated Donor HCT For FA Since 2006
CsA / MP Rapa / MMF
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Fanconi Anemia Thymic Shielding
Since 2003
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Thymus block Prior to HCT, CT is performed to locate the thymus
Thymus blocks attached to TBI stand brackets securing the lung compensators
Thymus Shielding
University of Minnesota
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Similar Survival after MSD HSCT and Alternative Donor HSCT for Standard Risk Patients with FA
92% Matched sibling, n=24
67% Alternative donor: high risk n=6 (MDS/Acute leukemia or renal failure)
87% Alternative donor: std risk, n=45
4 6 Months After HSCT
Cum
ulat
ive
Inci
denc
e
0.4
0.2
0.0
0.6
0.8
1.0
0 2 8 10 12 University of Minnesota
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y Matched Sibling Donors
Standard Risk FLU-CY
Alternative Donors
Standard Risk TBI 300+TS
Alternative Donors
High Risk TBI 300+TS
N 24 45 6
Engraftment 100% 93% 100%
Acute GVHD 4% 11% 17%
Chronic GvHD 8% 4% 0%
1 Year Survival 92% 87% 67%
Secondary Malignancies
2/45 = 4% (2 SCC)
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Neutrophil Recovery Cu
mul
ativ
e In
cide
nce,
%
Days
100
10
0
30
20
50
40
70
60
90
80
0
100
90
80
UCB mismatched, 79%
0 20 50
Eapen / Wagner et al. 10 30 40
PBPC matched, 96%
PBPC mismatched, 96% BM matched, 92%
BM mismatched, 94% 13 18
25
Slow recovery in adults and children Increased risk of graft failure
Adults
14%
Lancet Oncol 2010; 11: 653-60
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Cell dose is critical Correlation between recovery and cell dose
0 7 14 21 28 35 42 49
Days after UCBT
56 63 70 77
Neutrophil Engraftment by Cell Dose (x107/kg)
Target: >20 x 107/kg
Median cell dose transplanted: 3.6 x 107/kg in children
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-7 -6 -5 -4 -3 -2 -1 0 7 14
Speed of PMN Recovery
100
Advantages • Infusion timing
• Tracking progeny Limitations • Immunological
graft-graft interactions
BMBx BMBx
360
Days
Trial Design HSC835 Dose Escalation
• 0.3-0.9 x 108 NC/kg
• 0.9-2.7 x 108 NC/kg
• 2.7-8.1 x 108 NC/kg
• 8.1-24 x 108 NC/kg
CD34-
Cryopreserved
CD34+
-15
DUCBT Platform
Uncultured UCB 1
UCB 2
NC >1.5 x 107/kg (smaller unit)
HLA < 2 ag mm NC >1.5 x 107/kg (larger
unit)
TBI FLU FLU FLU
CY CY
Ex vivo culture begins
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HSC835 engraftment accelerates neutrophil and platelet recovery
Significant correlation between HSC835 CD34 dose and time to engraftment
HSC835 Engrafted (12/17 patients)
Unmanipulated Engrafted (5/17 patients)
Wagner et al. Submitted
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Patient Age
CY FLU TBI 300 cGy Engraft GVHD Survival COD
Outcomes in Adults
1 19.4 11 none Dead (2.2 y) SCC (1 y)
2 21.2 14 none Alive (5.3 y) -
3 24.1 16 none Alive (2.6 y) -
4 (MDS) 33.1 15 GI (stg 2) Alive (2.5 y) -
5 34.3 13 none Alive (2.0 y) -
6 (MDS) 26.1 38 none Dead (59 d) hem
7 (MDS) 28.6 22 GI, Liv (stg 4) Dead (57 d) GvH
8 (MDS) 25.2 30 none Dead (34 d) tox
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Fanconi Anemia Advanced MDS/Leukemia
HCT TCD BM
UCB
G-CSF
(Day 30)
(Day 180)
(ANC 2500)
CSA
MMF
FLU 35 FLU 35 FLU 35 FLU 35
-6 -8 -7 0 -5 -4 -3 -1
ATG ATG ATG ATG ATG
-2
BU 0.8 BU 0.8
CY 10 CY 10 CY 10 CY 10
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Overall Survival and Relapse FA MDS / Acute Leukemia
Cum
ulat
ive
Prop
ortio
n
2 Years
1.0 0.8 0.6 0.4 0.2 0.0
0 1 3 4 5
Survival: 50% (95% CI, 21-74%)
Relapse: 21% (95% CI, 1-44%)
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Impact of BRCA2 / Leukemia
2 Years
Cum
ulat
ive
Prop
ortio
n
BRCA2
0.2 0.0
0.6
0.8
1.0
0 1 3 4 5
II I
I I
No BRCA2
Two additional pts
BU/CY/FLU; single UCB
MDS, 6.5 months out, well BU/CY/FLU; single UCB
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Timing of Transplant When to consider alternatives
to transplant
Very poor organ function Kidney Cardiac
Pre existing infections
Lung Blood
Older Patient Age
>40 (sibling donor) >35 (unrelated donor)
Alternatives Androgens
Long term use of blood growth factor
Experimental therapy (gene therapy or novel transplant protocol)
No donor
Cancer
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Historical Observations
Conclusions • Transplant is associated with
high rate of solid tumors, particularly SCCs
•Association between GVHD [or its treatment] and SCCs
- 33-fold higher risk AGVHD - infinity higher risk CGVHD
Rosenberg, Blood 2005; 105: 67-73
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Relative to non transplanted FA patients
Earlier onset and higher frequency of SCC after BMT
Additional Findings
Median age 19 years (BMT) Association with grade 3-4 acute and extensive chronic GVHD
96% pts with aGVHD died
All SCC patients had h/o cGVHD
Median age 31 years (non BMT)
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Higher rate of SCC after BMT is due to
Hypothesis
• GVHD or its treatment Bonfim (Curitiba) • Conditioning regimen?
11 patients with cancer - Radiation
- Cyclophosphamide
- Busulfan
MTecdeialnl daegep1le8tyioeanrs
MediaTnBinI tdeorvsael (dBeM-T toeSsCcCa)la7tyioeanrs
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All patients transplanted at the U Minnesota from 1990 to 2012
• All donor sources
• 174 transplants
• 100 alive
• 95% contacted to verify current survival and cancer status
Patient Population
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Post-BMT Cancers
Pt/Gender Age Age Cancer Interval 2994, M 41.2 42.1 SCC larynx 0.9 yrs 7303, F 28.6 41.0 SCC sal gl 12.4 yrs 8443, F 19.4 20.5 SCC tongue 1.1 yrs 1680, M 16.8 32.3 SCC lung 15.5 yrs
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9/25/2012 31
Shaded areas show 95% confidence limits. Hatch marks show censor times in the Minnesota Cohort. Not shown is one SCC in Pre-Transplant FA cohorts at age 49.9 years.
NO significant difference in the rate of SCC, overall (P=0.96), or up to age 20 (P=0.94), or after age 20 (P=1.0); rate ratios are 0.8, 0.0, 0.9 with VERY broad limits.
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9/25/2012 32
Conclusions: • BMT using more modern treatment packages may
not be associated with an increased risk of cancer
• Cancer remains an important issue for long term FA survivors [with or without BMT] requiring heightened surveillance and improved treatments
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FA Roadmap Sh
ort
Inte
rmed
iate
Long
Clinical Trials in FA
T regulatory cells
FA HSC expansion AML targeted therapy
Thymic progenitor cells iPS cell derived FA HSC
Survivorship Clinic
Genetic Testing Center
Developmental Studies
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Assessment of GVHD and Dual Chimerism
Mycophenolate - 3 to + 30
G-CSF until ANC >2500/uL
Fludarabine 200 mg/m2
-3 -2 -1 0 7 14 21 28 -4 -8 -7 -6 -5 -9
sTBI 200 cGy
Day +28 BMBx
Cytoxan 50 mg/kg
University of Minnesota
Treg Unit 3
CSA - 3 to + 100 RAPA - 3 to + 100
HLA mismatched double UCBT
Doses on day 1 1 x 105/kg 3 x 105/kg 1 x 106/kg 3 x 106/kg
10 x 106/kg 30 x 106/kg 100 x
106/kg
Treg Dose Escalation
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Treg Expansion Culture Alternatives
KT64/86
Purified UCB CD4+25+
cell
10,000 RADS
CD28
CD3
TCR
Treg cell
Anti-CD3
Anti-CD28
Anti-CD3/28 beads
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Re-stimulat ion increases clin ical UCB nTreg yield w ithout decreasi ng Foxp3 or suppressive fu nction (n=3).
I Expansion I Day o
I IL 2
3
(300 /nll) Stimulate lvith
KT64/86
12
l ± Re-stimulation
\ \ ith KT64/86 1
19
1 Assay for phenotype
and suppression
10000 100 100 2843
N + 80 .. 80
c 60
c 1000 or-t m c. © ·- v-, ) ( c 0 60 nJ LL ·-0
v-, v-,
100 I c. N"""' ) (
w or-t 40 40 "'C c c. - u
'*' c. ::::s
V ' )
'*' 0 10 LL 20 20
1 0 0 RO Rl RO Rl RO Rl
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Higher Treg Dose Results in Greater Proportions of Treg in the PB
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Prevention of Acute GVHD Potency of Treg >3 x 106/kg vs Controls
Inci
denc
e
Days
CsA/MMF 62%
Treg/Siro/MMF 12%
80 100 0.0
0.4
0.6
0.8
1.0
0 20 40 60
Siro/MMF 48%
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Immune Reconstitution
Protect the thymus
Increase T progenitors
Eliminate post transplant immune suppression
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Thymic Protection and Increasing Thymic Progenitors
Culture conditions OP9-DL1 Flt3 IL7
thymus
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Gene Therapy
• Isolate and expand autologous FA HSC for gene correction
• iPS cell-derived HSC
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• Outcomes after Alternative Donor HSCT same as for MSD HSCT – engraftment, GVHD and survival similar
• High risk patients = advanced MDS (>5% blasts), acute leukemia, or renal failure have lower survival
• Lymphoid recovery is the biggest hurdle
Summary
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When to Transplant Adults with FA
• before advanced MDS or AML • before transfusions • before major infections
• Next steps – Eliminate use of steroids (AVN) – Shield ovaries
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Acknowledgements Fanconi Anemia Comprehensive Clinic
- Margy MacMillan, MD - Pat Fidler, RN -Heather Zierhut, MS - Lucie Turcot, MD – late effects - Anna Petryk, MD - endocrinology - Lynda Polgreen, MD - endocrinology - Frank Ondrey, MD - ENT - Rahel Ghebre, MD - gynecology - Sarah Jane Schwarzenberg, MD - gastroenterology - Jo-Anne Young, MD - infectious diseases - Ann Van Heest, MD – hand surgeon -neuropsychologists, ophthalmology, audiology, cardiology, pulmonology, nephrology, dentistry